This project will investigate the hypothesis that chronic fatigue syndrome (CFS) results from the inappropriate or excessive activation of mononuclear phagocytic cells by antigen. The subsequent release of cytokines from these mononuclear phagocytes produces the clinical spectrum of CFS. Normally, the activation of monocytes is an inefficient process, dependent on high concentrations of antigen which is pinocytosed or phagocytosed to be processed and presented by these cells. However, surface expression of Fc/epsilon/RII or CD23 on monocytes/macrophages has been proposed as functioning as a "capture molecule." In the additional presence of antigen-specific IgE, antigen will be internalized and presented in the presence of ~100-fold or more lower concentrations or antigen. CFS has been characterized by the presence of increased concentrations of IgE. Increased expression of Fc/epsilon/RII may occur as part of the immune response to viral infections or in atopic states, both of which have been proposed as being present in at least some CFS patients. Specific aim #1 will therefore utilize flow cytometry to quantify the expression of Fc/epsilon/RII on the surface of monocytes in patients with CFS. Specific Aim #2 will investigate the hypothesis that triggering of Fc/epsilon/RII on monocytes results in the production of the cytokines IL-1, TNF-alpha, and IL-6 - cytokines which may produce the clinical spectrum of CFS. We will compare the efficiency of non-specific antigen presentation (i.e., pinocytosis) with an IgE-Fc/epsilon/RII-specific process in inducing cytokine production. This will investigate the hypothesis that CFS may be characterized by a capacity to produce cytokines through this "capture molecule" at a concentration of antigen many times lower than that which would normally trigger monocytes. Finally, specific aim #3 will investigate the hypothesis that CFS is characterized by a tendency of T lymphocytes to synthesize IL-4 in response to antigens. IL-4 is responsible for the IgE isotype switch by B lymphocytes and induces Fc/epsilon/RII expression on monocytes. The inappropriate or excessive production of IL-4 will produce the clinical conditions which will allow chronic fatigue syndrome to develop according to the hypotheses of this grant.